Defining the transcriptomic and epigenetic blueprint of anti-viral T cell memory and the role of novel transcription factors in memory generation

抗病毒CD8 T细胞是免疫系统的重要组成部分，它可以对抗病毒感染，并调节病原体从体内清除。慢性病毒感染，如成年小鼠的持续性淋巴细胞性脉络膜脑膜炎病毒(LCMV)感染，以及人类的乙肝病毒(乙肝)、丙型肝炎病毒(HCV)和人类免疫缺陷病毒(HIV)感染，都会导致慢性炎症，随着时间的推移，最终会耗尽适应性宿主免疫系统，特别是CD8T细胞。相比之下，疱疹病毒如巨细胞病毒(CMV)以不活跃的潜伏形式持续存在并在宿主中共存，不会造成广泛的免疫失调。与其他病毒感染不同，CMV感染的控制在很大程度上依赖于一组独特的终末分化的病毒特异性效应T细胞的积累，即所谓的膨胀性T细胞，目前人们对此知之甚少。慢性病毒感染是人类面临的主要临床挑战，目前尚不清楚为什么不同的慢性感染会导致免疫控制策略中截然相反的T细胞反应。虽然已经描述了T细胞分化的几个方面，但确定记忆T细胞形成的关键属性和这一过程的通用转录蓝图一直是一个主要的挑战。我们将在小鼠模型中研究慢性LCMV和CMV感染后CD8 T细胞的反应。病毒感染后产生的记忆CD8 T细胞的转录和表观遗传学特征将使用最先进的基因组技术进行评估。在病毒感染早期出现的干细胞样T细胞的时间动态将使用Belz实验室提供的独特的报告小鼠品系来定义。缺乏转录因子的小鼠品系(IRF4-/-和Tox-/-Tox2-/-小鼠模型)将被用来了解这些转录因子在T细胞对慢性病毒感染的反应中的作用。此外，该项目的一个主要目标是描绘有助于长期保护性免疫的T细胞的核心细胞和分子蓝图，并了解不同的途径是如何产生的。为了提供对这些程序和途径的综合理解，我们将比较不同慢性病毒感染后产生的幼稚T细胞、干细胞样抗肿瘤T细胞和记忆CD8 T细胞的转录和表观遗传学特征。这将提供一个长期记忆T细胞的综合概况，在慢性环境中驱动保护。这种方法将导致发育转录蓝图，其中产生稳定和保护性的CD8T细胞记忆，即使在免疫失调的阴影下也是如此。生物信息学分析将侧重于识别CD8 T细胞记忆机制的独特组件，以及识别在不同病毒感染和抗肿瘤反应等多种情况下保存的统一核心程序。

Antiviral CD8+ T cells constitute a critical arm of immune system that fight virus infections and mediate pathogen clearance from the body. Chronic virus infections such as persistent lymphocytic choriomeningitis virus (LCMV) infection of adult mice, and hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections of humans induce chronic inflammatory conditions that ultimately exhaust the adaptive host immune system over time, in particular the CD8+ T cell. In contrast, herpesviruses such as cytomegalovirus (CMV) persist and coexist in the host in an inactive latent form and do not cause widespread immune dysregulation. Control of CMV infection, distinct from other virus infections, depends largely on the accumulation of a unique population of terminally-differentiated virus-specific effector CD8＋ T cells known as inflationary T cells, which currently are only poorly understood. Chronic virus infections constitute a major clinical challenge to humanity, and it remains unclear why different chronic infections result in diametrically opposing T cell responses in immune control strategies. Although several aspects of T cell differentiation have been described, defining key attributes of memory T cell formation and a universal transcriptional blueprint of this process has been a major challenge.CD8+ T cell responses following chronic LCMV and CMV infection in the mouse model will be studied. The transcriptional and epigenetic profile of the memory CD8+ T cells generated following virus infection will be assessed using state-of-the-art genomic technologies. The temporal dynamics of stem-cell like T cells that emerge early upon virus infection will be defined using unique reporter mouse strains available in Belz laboratory. Mouse strains that lack transcription factors (Irf4-/- and Tox-/-Tox2-/- mouse models) will be used to understand the role of these TFs in T cell responses to chronic virus infections. Moreover, a major objective of this project is to delineate a core cellular and molecular blueprint of T cells that contribute to long-term protective immunity and understand how different pathways are generated. To provide an integrated understanding of these programs and pathways, the transcriptional and epigenetic profile of naïve, stem-cell like anti-tumor T cells and memory CD8+ T cells generated following different chronic virus infections will be compared. This will provide an integrated profile of long-term memory T cells that drive protection in the chronic setting. This approach will lead to the developmental transcriptional blueprint in which stable and protective CD8+ T cells memory is generated, even in shadow of immune dysregulation. The bioinformatics analysis will be focused on identifying unique components of CD8+ T cell memory machinery, as well as, identifying a unified core program that is conserved in multiple settings such as different virus infections and anti-tumor responses.